Extracellular matrix secretion by cardiac fibroblasts Role of microRNA-29b and microRNA-30c

TY - JOUR

T1 - Extracellular matrix secretion by cardiac fibroblasts Role of microRNA-29b and microRNA-30c

AU - Abonnenc, Mélanie

AU - Nabeebaccus, Adam A

AU - Mayr, Ursula

AU - Barallobre-Barreiro, Javier

AU - Dong, Xuebin

AU - Cuello, Friederike

AU - Sur, Sumon

AU - Drozdov, Ignat

AU - Langley, Sarah R

AU - Lu, Ruifang

AU - Stathopoulou, Konstantina

AU - Didangelos, Athanasios

AU - Yin, Xiaoke

AU - Zimmermann, Wolfram-Hubertus

AU - Shah, Ajay M

AU - Zampetaki, Anna

AU - Mayr, Manuel

PY - 2013/10/25

Y1 - 2013/10/25

N2 - Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis. Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix secretion by cardiac fibroblasts. Methods and Results: Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry. miR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor, insulin-like growth factor 1, and pentraxin 3, 3 predicted targets of miR-29b. miR-29b also attenuated the cardiac fibroblast response to transforming growth factor-β. In contrast, miR-30c had little effect on extracellular matrix production but opposite effects regarding leukemia inhibitory factor and insulin-like growth factor 1. Both miRNAs indirectly affected cardiac myocytes. On transfection with pre-miR-29b, the conditioned medium of cardiac fibroblasts lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (α-actinin, cardiac myosin-binding protein C, and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium, whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c, and miR-30c, but not miR-29b, were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function. Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.

AB - Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis. Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix secretion by cardiac fibroblasts. Methods and Results: Mouse cardiac fibroblasts were transfected with pre-/anti-miR of miR-29b and miR-30c, and their conditioned medium was analyzed by mass spectrometry. miR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor, insulin-like growth factor 1, and pentraxin 3, 3 predicted targets of miR-29b. miR-29b also attenuated the cardiac fibroblast response to transforming growth factor-β. In contrast, miR-30c had little effect on extracellular matrix production but opposite effects regarding leukemia inhibitory factor and insulin-like growth factor 1. Both miRNAs indirectly affected cardiac myocytes. On transfection with pre-miR-29b, the conditioned medium of cardiac fibroblasts lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (α-actinin, cardiac myosin-binding protein C, and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium, whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c, and miR-30c, but not miR-29b, were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function. Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.

KW - Animals

KW - C-Reactive Protein

KW - Cells, Cultured

KW - Collagen

KW - Extracellular Matrix

KW - Fibroblasts

KW - Fibrosis

KW - Insulin-Like Growth Factor I

KW - Leukemia Inhibitory Factor

KW - Male

KW - Matrix Metalloproteinases

KW - Mice

KW - Mice, Inbred C57BL

KW - MicroRNAs

KW - Models, Animal

KW - Myocardium

KW - Proteomics

KW - Serum Amyloid P-Component

KW - Transforming Growth Factor beta

U2 - 10.1161/CIRCRESAHA.113.302400

DO - 10.1161/CIRCRESAHA.113.302400

M3 - SCORING: Journal article

C2 - 24006456

VL - 113

SP - 1138

EP - 1147

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 10

ER -